更全的杂志信息网

亚临床甲状腺功能减退对血脂水平的研究进展

更新时间:2016-07-05

甲状腺功能减退是常见的甲状腺疾病,可导致多种心脏疾病的发生,如冠状动脉粥样硬化性心脏病、心力衰竭[1]以及心脏舒缩功能异常[2,3]等,其机制与甲状腺功能减退时出现的相关激素水平的变化对血压、糖脂代谢及内皮功能等的影响密切相关。亚临床甲状腺功能减退(Subclinical hypothyroidism,SCH)是常见的内分泌疾病,系早期的、轻度的甲状腺功能减退;临床上将其定义为血清促甲状腺激素(thyroid stimulating hor⁃mone,TSH)水平升高,而血清游离甲状腺素及3-碘甲状腺原氨酸(FT4、FT3)正常的一种病理状态。流行病学显示一般人群SCH的患病率为4%~20%,但在60岁以上的老年女性,其患病率高达20%[4]。目前众多研究表明,促甲状腺素受体(TSHR)不仅表达于甲状腺,还表达在甲状腺外的组织如肝脏[5]、心肌组织[6]、脂肪组织[7,8]等,并且与内皮细胞损伤、动脉硬化等密切相关[9],并且左旋甲状腺素(L-T4)替代治疗可明显改善上述病理状态。血脂代谢异常与心血管疾病的发生密切相关,而SCH可引起总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density li⁃poprotein cholesterol,LDL-C)的水平升高,而高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDLC)的水平降低,并且LDL-C水平的升高及HDL-L水平的降低不仅促进动脉粥样硬化,也是相关心血管疾病发生的危险因素。但是目前关于SCH对血脂的影响仍存在争议,故正确认识SCH对血脂的影响以及L-T4替代治疗的效果,对患者的诊治和预后意义重大。

1 SCH与血脂的关系

近年研究发现,SCH患者较甲状腺功能正常组相比,TC、TG及LDL-C水平明显升高,HDL-C水平明显降低。纳入1 981例患者的波士顿研究中发现即使TSH水平低于10 mIU/L,SCH患者TC、TG、LDL-C水平仍是明显升高的[10];在另有一些研究中得出了相同的结果[11-13]。对年龄和性别进行分层的研究表明,女性SCH患者TC、LDL-C水平较男性高,HDL-C水平较男性低[14]。18岁以上的SCH患者的TC、LDL-C水平升高而HDL-C水平降低[15]。印度一项纳入5 342例SCH患者的临床研究中发现,SCH的患病率是14.7%,TSH与TC、LDL-C正相关而FT3、FT4与TC、LDL-C负相关[15]。在TSH>10 mIU/L的SCH患者中,也得出了相同的结果[15-16]。在一项调整了年龄、性别及体重的研究中也得出了类似的结果[17]。在一项纳入95位新诊断的中年SCH女性患者临床研究发现,匹配体重指数及年龄后,与甲状腺功能正常者相比,TC明显升高,HDL-C明显降低[16]。在尼泊尔一项纳入200名病例的对照研究中发现,SCH患者与正常组相比TC、LDL-C明显增加,但HDL-C无明显变化[18]。但是有一项近期研究得出了不同结果,SCH患者TG及其与HDL-C的比值较甲状腺功能正常者明显增加,而TC、LDL-C明显降低[19]。另有研究表明SCH组仅表现为TG水平升高和HDL-C水平的降低,LDL-C无明显变化[20]

在我国一项纳入741名患者横断面研究中发现,SCH组LDL-C,载脂蛋白β(Apoβ)和同型半胱氨酸(Hcy)水平明显增加,而HDL-C水平明显降低,在调整性别、年龄及吸烟等因素后,多元回归分析显示TSH水平 TG,TC,LDL-C,Apoβ,Hcy水平正相关,而与HDL-C水平负相关[21]。另有研究发现,即使甲状腺功能正常时,血脂也会受到影响,此外一些因素比如吸烟、肥胖胰岛素抵抗等会加重TSH对血脂的影响[22]。一项平均年龄8岁左右的临床研究中发现,SCH患者与正常对照组比较TC、LDL-C、以及TC/HDL-C和LDLC/HDL-C比值明显升高,但这种差异并未出现在SCH两个亚组(TSH>10 mIU/L及TSH=4.210 mIU/L)中[23]。在波兰一项纳入187名肥胖妇女临床研究中发现,TC,LDL-C和TG以及LDL-C/HDL-C值在SCH组明显升高[24]。特罗姆瑟一项纳入5 143例患者的病例研究中发现,84例SCH患者的血清LDL-C及Apo A1与正常对照组比较水平明显降低,但是SCH女性患者TC明显升高[25]。另一些研究发现,SCH对血脂水平无影响。纳入8 228例患者临床研究中表明,虽然SCH患者平均胆固醇水平较甲状腺功能正常者高,但是无明显差异,在调整年龄、性别、种族及排除使用降脂药物等干扰因素外,仍得出相同结果[26]。在一项1 212例的横断面研究中发现,SCH在一般人口中患病率为19.7%,血清TG及C反应蛋白水平明显增高,而TC与LDL-C无明显变化[27]。在TSH<10 mIU/L SCH 患者中,血脂未见明显变化[15]。更有研究表明,在调整种族、性别、年龄等差异配后,SCH患者与甲状腺功能正常者相比,TC、LDL-C、HDL-C水平亦无明显差异[26]。还有一些研究发现,中年SCH女性患者,TC与LDL-C无明显变化,而与对照组相比TG水平明显升高,HDL-C水平明显降低[28-29]。在一项纳入1 112例合并有糖尿病SCH患者研究表明,TC、TG、LDL-C、HDL-C的水平在SCH患者与甲状腺功能正常者之间并无显著差异[30];在另一项不合并糖尿病的临床研究中仍得出了相同的结果[31]

还有研究发现,脂蛋白(Lipoprotein-A,Lpo-A)与载脂蛋白水平变化是心血管疾病发生的危险因素,与SCH也密切相关[32]。57名孕妇的横断面研究中发现,SCH组载脂蛋白A(Apolipoprotein-A,Apo-A)水平与甲功正常组相比明显降低[33]。另有研究表明,Apo-A1和HDL-C水平在SCH组明显降低,并且与血清同型半胱氨酸水平负相关,同型半胱氨酸可能抑制上述指标的抗氧化能力,造成心血管功能破坏[34]。有研究显示,与正常对照组相比TSH,载脂蛋白B-48(ApoB-48)及TG水平明显升高,甲状腺功能对ApoB-48水平的影响与对TC,LDL-C和TG影响相似,血清ApoB-48水平升高与动脉硬化密切相关[35]。但是另一些研究结果与上述相反,例如LpoA水平在SCH组中增高,但是与正常对照组比较无统计学意义[36]。SCH患者血脂水平变化在不同文献研究中结果不尽相同,可能与纳入病例的种族、年龄、性别、体重指数、吸烟等因素的有关,也可能是由于TSH和甲状腺素对血脂的复杂作为机制所致。

问题解决第三课时的教学我主要采用四人小组合作模式,让学生自己去探索讨论,体会如何按比例分配,从而掌握知识。我的设计流程如下:

2 左旋甲状腺素替代治疗后血脂水平改变

目前,对于SCH患者L-T4替代治疗对血脂影响也存在争议。有研究表明,TC及LDL-C在L-T4替代治疗后明显降低,但ApoB及LpoA无明显改变[37]。在一项纳入30名停经前妇女的SCH患者临床研究中发现,在L-T4替代治疗(50-100 ug/d)6月后,SCH患者与正常对照组TC、LDL-C及TC/HDL-C比值明显降低[38]。在一项纳入100例SCH患者(平均TSH浓度6.6 mIU/L),行L-T4(100 ug/d)替代治疗12周后与安慰剂组比较显示,TC、LDL-C及腰臀比明显降低[39]。另有研究表明,SCH患者在小剂量L-T4治疗后LDL-C、TC、non-HDL-C及LDL-C/HDL-C比值明显降低[40]。在一项平均年龄在9岁左右临床研究发现,HDL-C较正常组相比明显降低而TG/HDL-C的值明显升高,在行甲状腺素替代治疗2年后上述血脂水平改变明显被改善[41]。研究表明,ApoB-100在L-T4替代治疗后明显降低[25]。TSH与TC,TG和ApoB正相关[42]。L-T4替代治疗后TC及ApoB明显降低[43]。ApoB-48作为乳糜微粒组成部分,与动脉粥样硬化密切相关,研究表明,L-T4替代治疗后,SCH患者TC,TG及ApoB和ApoB-48明显降低[44]。在波兰一项纳入187名肥胖妇女临床研究中发现,TC,LDL-C和TG以及LDL-C/HDL-C的比值在SCH组明显升高6个月的L-T4替代治疗后上述指标均明显改善[24]。L-T4替代治疗后SCH患者与安慰剂组比较ApoB水平明显降低[25]。但在一项纳入63名SCH患者临床研究中发现,L-T4替代治疗48周后,替代治疗组与安慰剂组相比仅出现LDL-C明显降低,其余血脂指标如HDL-C、TG、Apo-A1等均未见明显变化[45]。也有研究表明,L-T4替代治疗后TC与TG无变化[46]。L-T4替代治疗3个月对改善SCH患者血脂水平未见显著的效果[47]。还有研究发现,L-T4替代治疗,对TC,LDLC,HDL-C,TG及ApoB均无明显改善[48]。尽管 L-T4替代治疗对血脂水平影响存在差异,但仍有有研究表明,当TSH>10 mIU/L时,L-T4替代治疗是必须的[49],这与2013年欧洲甲状腺协会对于SCH患者推荐治疗方案一致[50]

3 SCH患者血脂水平变化的可能影响机制

SCH对血脂影响可能与TSH及甲状腺素两者作用有关。研究表明,位于细胞内质网内的3-羟基-3-甲基戊二酰辅酶还原酶(HMGCR),是胆固醇合成途径中最重要的限速酶,通过调节该酶可维持体内胆固醇稳定[51]。SCH患者临床检验最突出表现为TSH增高,TSH增高通过激活cAMP/PKA通路增强HMGCR的表达,不仅加速胆固醇的合成,使血浆中胆固醇水平升高,而且TSH还能抑制HMGCR磷酸化,使有活性HMGCR浓度增高,促进胆固醇的合成,影响血脂水平[5,51,52]。此外,血脂水平变化与甲状腺素的作用也关系密切;研究表明,甲状腺素能够直接促进低密度脂蛋白受体基因的转录,从而导致低密度脂蛋白受体的表达显著增加[53],加速血浆中胆固醇的清除;还能通过降低循环中前蛋白转化酶枯草溶菌素9浓度,从而增加细胞表面低密度脂蛋白受体的表达,促进血浆中胆固醇的清除,降低胆固醇水平[54]

4 结束语

大多数的研究表明,SCH与血脂水平的变化,尤其是TC,TG,LDL-C的升高及HDL-C水平的降低密切相关,且甲状腺素替代治疗不仅有益于血脂水平的恢复,更减少了与SCH相关的多种疾病的发生风险。

吴文表示:在中国伟大的改革开放历史进程中,私营经济已经初步完成了协助公有经济实现跨越式发展的重大阶段性历史重任。下一步,私营经济不宜继续盲目扩大,一种全新形态、更加集中、更加团结、更加规模化的公私混合制经济,将可能在社会主义市场经济社会的新发展中,呈现越来越大的比重。

参考文献:

[1] Biondi B.Mechanisms in endocrinology:Heart failure and thy⁃roid dysfunction[J].Eur J Endocrinol,2012,167(5):609-618.

[2] Biondi B Cooper D S.The clinical significance of subclinical thyroid dysfunction[J].Endocr Rev,2008,29(1):76-131.

[3] Tiryakioglu SK ,Tiryakioglu O ,Ari H,et al.Left ventricular longitudinal myocardial function in overt hypothyroidism:a tissue Doppler echocardiographic study[J].Echocardiogra⁃phy,2010,27(5):505-511.

[4] Cooper D SBiondi B.Subclinical thyroid disease[J].Lancet,2012,379(9821)1142-1154.

[5] Zhang W ,Tian L M ,Han Y,et al.Presence of thyrotropin re⁃ceptor in hepatocytes:not a case of illegitimate transcription[J].JCell Mol Med,2009,13(11-12):4636-4642.

[6] Huang W ,Xu J,Jing F,et al.Functional thyrotropin recep⁃tor expression in the ventricle and the effects on ventricular BNPsecretion[J].Endocrine,2014,46(2):328-339.

[7] Wozniak SE ,Gee L L,Wachtel M S,et al.Adipose tissue:the new endocrine organ?A review article[J].Dig Dis Sci,2009,54(9):1847-1856.

[8] Fietta P Delsante G.Focus on adipokines[J].Theor Biol Fo⁃rum,2013,106(1-2):103-129.

[9] Gao C ,Li T ,Liu J,et al.Endothelial Functioning and Hemo⁃dynamic Parameters in Rats with Subclinical Hypothyroid and the Effects of Thyroxine Replacement[J].PLoS One,2015,10(7).

[10] Walsh JP ,Bremner A P ,Bulsara M K,et al.Thyroid dys⁃function and serum lipids:a community-based study[J].Clin Endocrinol(Oxf),2005,63(6):670-675.

[11] Rizos C V ,Elisaf M SLiberopoulos E N.Effects of thyroid dysfunction on lipid profile[J].Open Cardiovasc Med J,2011(5):76-84.

[12] Lioudaki E ,Mavroeidi NG ,Mikhailidis DP,et al.Subclini⁃cal hypothyroidism and vascular risk:an update[J].Hor⁃mones(Athens),2013,12(4):495-506.

[13] Laway B A ,War F A ,Shah S,et al.Alteration of lipid pa⁃rameters in patients with subclinical hypothyroidism[J].Int JEndocrinol Metab,2014,12(3).

[14] Tognini S,Polini A ,Pasqualetti G,et al.Age and gender substantially influence the relationship between thyroid sta⁃tus and the lipoprotein profile:results from a large cross-sectional study[J].Thyroid,2012,22(11):1096-1103.

[15] Marwaha RK ,Tandon N ,Garg M K,et al.Dyslipidemia in subclinical hypothyroidism in an Indian population[J].Clin Biochem,2011,44(14-15):1214-1217.

[16] Hernandez-Mijares A ,Jover A ,Bellod L,et al.Relation be⁃tween lipoprotein subfractions and TSH levels in the cardio⁃vascular risk among women with subclinical hypothyroidism[J].Clin Endocrinol(Oxf),2013,78(5):777-782.

[17] Lee Y K ,Kim J E ,Oh H J,et al.Serum TSH level in healthy Koreans and the association of TSH with serum lip⁃id concentration and metabolic syndrome[J].Korean J In⁃tern Med,2011,26(4):432-439.

[18] Kc R ,Khatiwada S,Deo Mehta K,et al.Cardiovascular Risk Factors in Subclinical Hypothyroidism:A Case Control Study in Nepalese Population[J].JThyroid Res,2015.

[19] James SR ,Ray L,Ravichandran K,et al.High atherogenic index of plasma in subclinical hypothyroidism:Implications in assessment of cardiovascular disease risk[J].Indian JEn⁃docrinol Metab,2016,20(5):656-661.

[20] Erem C ,Suleyman A K ,Civan N,et al.The effect of L-thy⁃roxine replacement therapy on ischemia-modified albumin and malondialdehydelevelsinpatientswithovertand subclin⁃icalhypothyroidism[J].Endocr Res,2016,41(4):350-360.

[21] Wu J,Tao Y ,Gu H,et al.Association Between Cardiovas⁃cular Risk Factors and Serum Thyrotropin Concentration Among Healthy Chinese Subjects and Subjects with Unsus⁃pected Subclinical Hypothyroidism[J].Clin Lab,2016,62(5):807-814.

[22] Pearce E N.Update in lipid alterations in subclinical hypo⁃thyroidism[J].JClin Endocrinol Metab,2012,97(2):326-333.

[23] Unal E ,Akin A ,Yildirim R,et al.Subclinical hypothyroid⁃ism in children may lead to dyslipidemia and increased ca⁃rotid intima-media thickness[J].JClin Res Pediatr Endocri⁃nol,2016.

[24] Adamarczuk-Janczyszyn M ,Zdrojowy-Welna A ,Rogala N,et al.Evaluation of Selected Atherosclerosis Risk Factors in Women with Subclinical Hypothyroidism Treated with LThyroxine[J].Adv Clin Exp Med,2016,25(3):457-463.

[25] Iqbal A ,Jorde R Figenschau Y.Serum lipid levels in rela⁃tion to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism:the Tromso Study[J].J Intern Med,2006,260(1):53-61.

[26] Hueston W J Pearson W S.Subclinical hypothyroidism and the risk of hypercholesterolemia[J].Ann Fam Med,2004,2(4):351-355.

[27] Kvetny J,Heldgaard PE ,Bladbjerg E M,et al.Subclinical hypothyroidism is associated with a low-grade inflamma⁃tion,increased triglyceride levels and predicts cardiovascu⁃lar disease in males below 50 years[J].Clin Endocrinol(Oxf),2004,61(2):232-238.

[28] Mikhailidis D P,Elisaf M ,Rizzo M,et al."European panel on low density lipoprotein(LDL)subclasses":a statement on the pathophysiology,atherogenicity and clinical signifi⁃cance of LDL subclasses[J].Curr Vasc Pharmacol,2011,9(5):533-571.

[29] Mikhailidis D P,Elisaf M ,Rizzo M,et al."European panel on low density lipoprotein(LDL)subclasses":a statement on the pathophysiology,atherogenicity and clinical signifi⁃cance of LDL subclasses:executive summary[J].Curr Vasc Pharmacol,2011,9(5):531-532.

[30] Diez JJIglesias P.Serumcholesterol and triglyceride concen⁃trations in diabetic patients with subclinical hypothyroidism[J].Endocrinol Nutr,2014,61(8):419-425.

[31] Alamdari S,Amouzegar A ,Tohidi M,et al.Hypothyroidism and Lipid Levels in a Community Based Study(TTS)[J].Int JEndocrinol Metab,2016,14(1)e22827.

[32] Adrees M ,Gibney J,El-Saeity N,et al.Effects of 18 months of L-T4 replacement in women with subclinical hy⁃pothyroidism[J].Clin Endocrinol(Oxf),2009,71(2):298-303.

[33] Cai JZhang M.Variation tendency in serum high density li⁃poprotein cholesterol and apolipoprotein A-Iin different thy⁃roid function status during pregnancy[J].Beijing Da Xue Xue Bao,2015,47(6):910-913.

[34] Yang N ,Yao Z ,Miao L,et al.Homocysteine diminishes apolipoprotein A-I function and expression in patients with hypothyroidism:a cross-sectional study[J].Lipids Health Dis,2016(15):123.

[35] Mugii S,Hanada H ,Okubo M,et al.Thyroid function influ⁃ences serum apolipoprotein B-48 levels in patients with thy⁃roid disease[J].JAtheroscler Thromb,2012,19(10):890-896.

[36] Toruner F,Altinova A E ,Karakoc A,et al.Risk factors for cardiovascular disease in patients with subclinical hypothy⁃roidism[J].Adv Ther,2008,25(5):430-437.

[37] Caraccio N,Ferrannini E,Monzani F.Lipoprotein profile in subclinical hypothyroidism:response to levothyroxine re⁃placement,a randomized placebo-controlled study[J].J Clin Endocrinol Metab,2002,87(4):1533-1538.

[38] Serter R,Demirbas B,Korukluoglu B,et al.The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism[J].J Endocrinol Invest,2004,27(10):897-903.

[39] Razvi S,Ingoe L,Keeka G,et al.The beneficial effect of L-thyroxine on cardiovascular risk factors,endothelial func⁃tion,and quality of life in subclinical hypothyroidism:ran⁃domized,crossover trial[J].JClin Endocrinol Metab,2007,92(5):1715-1723.

[40] Tagami T ,Tamanaha T ,Shimazu S,et al.Lipid profiles in the untreated patients with Hashimoto thyroiditis and the ef⁃fects of thyroxine treatment on subclinical hypothyroidism with Hashimoto thyroiditis[J].Endocr J,2010,57(3):253-258.

[41] Cerbone M ,Capalbo D ,Wasniewska M,et al.Effects of L-thyroxine treatment on early markers of atherosclerotic dis⁃ease in children with subclinical hypothyroidism[J].Eur J Endocrinol,2016,175(1):11-19.

[42] Teixeira Pde F,Reuters V S,Ferreira M M,et al.Lipid pro⁃filein different degreesof hypothyroidismand effects of levo⁃thyroxine replacement in mild thyroid failure[J].Transl Res,2008,151(4):224-231.

[43] Ito M ,Arishima T ,Kudo T,et al.Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients[J].JClin Endocrinol Metab,2007,92(2):608-611.

[44] Ito M ,Kitanaka A ,Arishima T,et al.Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients[J].Endocr J,2013,60(1):65-71.

[45] Meier C ,Staub JJ,Roth CB,et al.TSH-controlled L-thy⁃roxine therapy reduces cholesterol levels and clinical symp⁃toms in subclinical hypothyroidism:a double blind,place⁃bo-controlled trial(Basel Thyroid Study)[J].JClin Endocri⁃nol Metab,2001,86(10):4860-4866.

[46] Nagasaki T ,Inaba M ,Yamada S,et al.Decrease of brachi⁃al-ankle pulse wave velocity in female subclinical hypothy⁃roid patients during normalization of thyroid function:a dou⁃ble-blind,placebo-controlled study[J].Eur J Endocrinol,2009,160(3):409-415.

[47] Arinzon Z ,Zuta A ,Peisakh A,et al.Evaluation response and effectiveness of thyroid hormone replacement treatment on lipid profileand function in elderly patientswith subclini⁃cal hypothyroidism[J].Arch Gerontol Geriatr,2007,44(1):13-19.

[48] Anagnostis P ,Efstathiadou Z A ,Slavakis A,et al.The ef⁃fect of L-thyroxine substitution on lipid profile,glucose ho⁃meostasis,inflammation and coagulation in patients with subclinical hypothyroidism[J].Int J Clin Pract,2014,68(7):857-863.

[49] Jonklaas J,Bianco A C ,Bauer A J,et al.Guidelines for the treatment of hypothyroidism:prepared by the american thy⁃roid association task force on thyroid hormone replacement[J].Thyroid,2014,24(12):1670-1751.

[50] Pearce S H ,Brabant G ,Duntas L H,et al.2013 ETA Guideline:Management of Subclinical Hypothyroidism[J].Eur Thyroid J,2013,2(4):215-228.

[51] Zhang X ,Song Y ,Feng M,et al.Thyroid-stimulating hor⁃mone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver[J].J Lipid Res,2015,56(5):963-971.

[52] Tian L,Song Y,Xing M,et al.A novel role for thyroid-stim⁃ulating hormone:up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding pro⁃tein pathway[J].Hepatology,2010,52(4):1401-1409.

[53] Lopez D ,Abisambra Socarras JF,Bedi M,et al.Activation of thehepatic LDLreceptor promoter by thyroid hormone[J].Biochim Biophys Acta,2007,1771(9):1216-1225.

[54] Bonde Y,Breuer O ,Lutjohann D,et al.Thyroid hormone re⁃duces PCSK9 and stimulates bile acid synthesis in humans[J].JLipid Res,2014,55(11):2408-2415.

宫宁宁,宫婷婷
《甘肃科技纵横》 2018年第05期
《甘肃科技纵横》2018年第05期文献

服务严谨可靠 7×14小时在线支持 支持宝特邀商家 不满意退款

本站非杂志社官网,上千家国家级期刊、省级期刊、北大核心、南大核心、专业的职称论文发表网站。
职称论文发表、杂志论文发表、期刊征稿、期刊投稿,论文发表指导正规机构。是您首选最可靠,最快速的期刊论文发表网站。
免责声明:本网站部分资源、信息来源于网络,完全免费共享,仅供学习和研究使用,版权和著作权归原作者所有
如有不愿意被转载的情况,请通知我们删除已转载的信息 粤ICP备2023046998号